The primary targets for HIV infection are CD4+ T lymphocytes and cells of the macrophage-monocyte lineage. Infection of T cells leads to their destruction and profound immunosuppression, while infection of macrophage- monocytes does not generally cause cytopathology, but may represent a sanctuary for the virus, serving as a reservoir for HIV persistence, spread and continual infection of T cells in the face of a significant, early immune response against viral antigens. Macrophages are also the likely routes of HIV infection of the central nervous system. The mechanisms by which virus-infected macrophages evade the host immune response are unknown. Unless they are elucidated, the pathogenesis of AIDS will not be fully understood and the prevention or therapy of HIV infections by immunologic means may not be achieved. The studies proposed are designed to systematically determine the mechanisms by which retroviral infection of macrophage lineage cells evades host immune responses and to identify the circumstances in which host immunity can be made capable of eliminating the infected cells. This will be approached using a novel experimental system developed in our laboratory involving Friend virus-induced erythroleukemias in mice. We have demonstrated that virus infection of macrophages occurs and is a critical factor in the pathogenesis of this disease. The conditions, the host is able to mount an immune response that eradicates the virus infected macrophages and this leads to leukemia regression. We have also found that CNS macrophages are productively infected with virus in this system, and that these infected cells are absent in regressor animals. This system thus permits identification of the factors involved in retroviral escape from host immune responses by establishment of a sanctuary infection in macrophages, as occurs in progressor animals. Moreover, it uniquely permits identification of the mechanisms by which the immune system can successfully eradicate infected macrophages and bring the disease under control, as occurs in regressor animals. This will be accomplished by: 1) determining if the viral and MHC antigens expressed on infected cells of the macrophage lineage differ from those on infected erythroid, lymphoid or fibroblastic cells; 2) determining whether expression of viral and MHC antigens on infected macrophages is modulated by cytokines, including GM-CSF, TNF-alpha, IFN's; and, 3) determining whether infected macrophages differ from other infected lineages in susceptibility to cell-mediated immune effectors.